title: Knockdown of β-catenin with dicer-substrate siRNAs reduces liver tumor burden in vivo.
abstract: Despite progress in identifying molecular drivers of cancer, it has been difficult to translate this knowledge into new therapies, because many of the causal proteins cannot be inhibited by conventional small molecule therapeutics. RNA interference (RNAi), which uses small RNAs to inhibit gene expression, provides a promising alternative to reach traditionally undruggable protein targets by shutting off their expression at the messenger RNA (mRNA) level. Challenges for realizing the potential of RNAi have included identifying the appropriate genes to target and achieving sufficient knockdown in tumors. We have developed high-potency Dicer-substrate short-interfering RNAs (DsiRNAs) targeting β-catenin and delivered these in vivo using lipid nanoparticles, resulting in significant reduction of β-catenin expression in liver cancer models. Reduction of β-catenin strongly reduced tumor burden, alone or in combination with sorafenib and as effectively as DsiRNAs that target mitotic genes such as PLK1 and KIF11. β-catenin knockdown also strongly reduced the expression of β-catenin-regulated genes, including MYC, providing a potential mechanism for tumor inhibition. These results validate β-catenin as a target for liver cancer therapy and demonstrate the promise of RNAi in general and DsiRNAs in particular for reaching traditionally undruggable cancer targets.
authors.affiliation: Dicerna Pharmaceuticals, Watertown, Massachusetts, USA.
authors.forename: Henryk
authors.initials: H
authors.lastname: Dudek
authors.affiliation: 1] Dicerna Pharmaceuticals, Watertown, Massachusetts, USA [2] Current addresses: Shire Human Genetic Therapies, Lexington, Massachusetts, USA (S.K.B.); Acceleron Pharma, Cambridge, Massachusetts, USA (M.L.); Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, USA (Y.L.); Medivation, San Francisco, California, USA (D.H.W.).
authors.forename: Darren H
authors.initials: DH
authors.lastname: Wong
authors.affiliation: Dicerna Pharmaceuticals, Watertown, Massachusetts, USA.
authors.forename: Rokhand
authors.initials: R
authors.lastname: Arvan
authors.affiliation: Dicerna Pharmaceuticals, Watertown, Massachusetts, USA.
authors.forename: Anee
authors.initials: A
authors.lastname: Shah
authors.affiliation: Dicerna Pharmaceuticals, Watertown, Massachusetts, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Wortham
authors.affiliation: Dicerna Pharmaceuticals, Watertown, Massachusetts, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Ying
authors.affiliation: Dicerna Pharmaceuticals, Watertown, Massachusetts, USA.
authors.forename: Rohan
authors.initials: R
authors.lastname: Diwanji
authors.affiliation: Dicerna Pharmaceuticals, Watertown, Massachusetts, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Dicerna Pharmaceuticals, Watertown, Massachusetts, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Holmes
authors.affiliation: Dicerna Pharmaceuticals, Watertown, Massachusetts, USA.
authors.forename: Hailin
authors.initials: H
authors.lastname: Yang
authors.affiliation: Dicerna Pharmaceuticals, Watertown, Massachusetts, USA.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Cyr
authors.affiliation: Dicerna Pharmaceuticals, Watertown, Massachusetts, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Dicerna Pharmaceuticals, Watertown, Massachusetts, USA.
authors.forename: Aalok
authors.initials: A
authors.lastname: Shah
authors.affiliation: Dicerna Pharmaceuticals, Watertown, Massachusetts, USA.
authors.forename: Ruchir
authors.initials: R
authors.lastname: Farkiwala
authors.affiliation: 1] Dicerna Pharmaceuticals, Watertown, Massachusetts, USA [2] Current addresses: Shire Human Genetic Therapies, Lexington, Massachusetts, USA (S.K.B.); Acceleron Pharma, Cambridge, Massachusetts, USA (M.L.); Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, USA (Y.L.); Medivation, San Francisco, California, USA (D.H.W.).
authors.forename: Michael
authors.initials: M
authors.lastname: Lee
authors.affiliation: 1] Dicerna Pharmaceuticals, Watertown, Massachusetts, USA [2] Current addresses: Shire Human Genetic Therapies, Lexington, Massachusetts, USA (S.K.B.); Acceleron Pharma, Cambridge, Massachusetts, USA (M.L.); Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, USA (Y.L.); Medivation, San Francisco, California, USA (D.H.W.).
authors.forename: Yiting
authors.initials: Y
authors.lastname: Li
authors.affiliation: Integrated DNA Technologies, Coralville, Iowa, USA.
authors.forename: Garrett R
authors.initials: GR
authors.lastname: Rettig
authors.affiliation: Integrated DNA Technologies, Coralville, Iowa, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Collingwood
authors.affiliation: 1] Dicerna Pharmaceuticals, Watertown, Massachusetts, USA [2] Current addresses: Shire Human Genetic Therapies, Lexington, Massachusetts, USA (S.K.B.); Acceleron Pharma, Cambridge, Massachusetts, USA (M.L.); Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, USA (Y.L.); Medivation, San Francisco, California, USA (D.H.W.).
authors.forename: Sujit K
authors.initials: SK
authors.lastname: Basu
authors.affiliation: Integrated DNA Technologies, Coralville, Iowa, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Behlke
authors.affiliation: Dicerna Pharmaceuticals, Watertown, Massachusetts, USA.
authors.forename: Bob D
authors.initials: BD
authors.lastname: Brown
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D051176:beta Catenin; D043244:Ribonuclease III